Increased flux of the plant sterols campesterol and sitosterol across a disrupted blood brain barrier

The intact blood-brain barrier in mammalians prevents exchange of cholesterol loaden particles between periphery and brain and thus nearly all cholesterol in this organ originates from de novo synthesis. Dietary cholesterol homologues from plants, campesterol and sitosterol, are known to get enriched to some extent in the mammalian brain. We recently showed that Pdgfbret/ret mice, with a pericyte deficiency and a leaking blood-brain barrier phenotype, have significantly higher levels of plant sterols in the brain compared to their heterozygous Pdgfbret/+ controls keeping the integrity of the blood-brain barrier (BBB). In order to further study the protective functionality of the BBB we synthesized a mixture of [2H6]campesterol/sitosterol and fed it for 10-40 days to genetically different types of animals. There was a significant enrichment of both deuterium stable isotope labeled plant sterols in the brain of both strains of mice, however, with a lower enrichment in the controls. As expected, the percentage and absolute enrichment was higher for [2H6]campesterol than for the more lipophilic [2H6]sitosterol. The results confirm that a leaking BBB causes increased flux of plant sterols into the brain. The significant flux of the labeled plant sterols into the brain of the control mice illustrates that the presence of an alkyl group in the 24-position of the steroid side chain markedly increases the ability of cholesterol to pass an intact BBB. We discuss the possibility that there is a specific transport mechanism involved in the flux of alkylated cholesterol species across the BBB.